SUMO1 modification stabilizes CDK6 protein and drives the cell cycle and glioblastoma progression.
SUMO1 modification stabilizes CDK6 protein and drives the cell cycle and glioblastoma progression.
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DOI：
10.1038/ncomms5234
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发表时间：
2014-06-23
影响因子：
16.6
通讯作者：
Hao, Chunhai
中科院分区：
文献类型：
--
作者：
Bellail, Anita C.;Olson, Jeffrey J.;Hao, Chunhai
泛素化通过周期蛋白的周期性降解来控制周期蛋白依赖性激酶（CDK）活性的振荡，从而促进有序的细胞周期进程；然而，在整个细胞周期中维持CDK蛋白水平恒定的机制尚不清楚。在这里，我们发现CDK6在胶质母细胞瘤中被小泛素样修饰物-1 （SUMO1）修饰，并且CDK6的sumoylation稳定了蛋白质并驱动了癌症发生和进展的细胞周期。CDK6也是泛素的底物；然而，CDK6在赖氨酸216位点的sumoylation阻断了其在赖氨酸147位点的泛素化，并抑制了泛素介导的CDK6降解。在整个细胞周期中，CDK1磷酸化sumo特异性酶，泛素偶联酶9 (UBC9)，进而在有丝分裂期间介导CDK6的sumo化；CDK6在G1期保持转录，并通过G1/S转变驱动细胞周期。因此，SUMO1-CDK6偶联是细胞周期控制的一种机制，抑制SUMO1-CDK6偶联可能为胶质母细胞瘤的治疗提供一种策略。
Ubiquitination governs oscillation of cyclin-dependent kinase (CDK) activity through a periodic degradation of cyclins for orderly cell cycle progression; however, the mechanism that maintains the constant CDK protein levels throughout the cell cycle remains unclear. Here we show that CDK6 is modified by small ubiquitin-like modifier-1 (SUMO1) in glioblastoma, and that CDK6 sumoylation stabilizes the protein and drives the cell cycle for the cancer development and progression. CDK6 is also a substrate of ubiquitin; however, CDK6 sumoylation at Lys 216 blocks its ubiquitination at Lys 147 and inhibits the ubiquitin-mediated CDK6 degradation. Throughout the cell cycle, CDK1 phosphorylates the SUMO-specific enzyme, ubiquitin-conjugating enzyme9 (UBC9) that in turn mediates CDK6 sumoylation during mitosis; CDK6 remain sumoylated in G1 phase and drives the cell cycle through G1/S transition. Thus, SUMO1-CDK6 conjugation constitutes a mechanism of cell cycle control and inhibition of this sumoylation pathway may provide a strategy for treatment of glioblastoma.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.8
作者：
Bertolotto, Corine;Lesueur, Fabienne;Bressac-de Paillerets, Brigitte
通讯作者：
Bressac-de Paillerets, Brigitte
DOI：
10.1126/science.1212728
发表时间：
2012-01-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kessler JD;Kahle KT;Sun T;Meerbrey KL;Schlabach MR;Schmitt EM;Skinner SO;Xu Q;Li MZ;Hartman ZC;Rao M;Yu P;Dominguez-Vidana R;Liang AC;Solimini NL;Bernardi RJ;Yu B;Hsu T;Golding I;Luo J;Osborne CK;Creighton CJ;Hilsenbeck SG;Schiff R;Shaw CA;Elledge SJ;Westbrook TF
通讯作者：
Westbrook TF
影响因子：
11.2
作者：
Hu MG;Deshpande A;Enos M;Mao D;Hinds EA;Hu GF;Chang R;Guo Z;Dose M;Mao C;Tsichlis PN;Gounari F;Hinds PW
通讯作者：
Hinds PW
影响因子：
7.3
作者：
Golebiowski, Filip;Matic, Ivan;Hay, Ronald T.
通讯作者：
Hay, Ronald T.